Pantothenic acid intermediates and process for their production



Patented Aug. 22, 1950 PANTQTHENIC ACID. IN TERMEDIATES AND PROCESS FORTHEIR- PRODUCTION Stanton A. Harris, Westfield, and Karl Folkers,Plainfield, N. J., assignors to Merck & 00., Inc., Rahway, N. J acorporation of New Jersey No Drawing. Application July 14, 1945, SerialNo. 605,193, which is a division of application Serial No. 386,942,April 14, 1941. Divided and this application March 3, 1948, Serial No.12,894

Claims.

This invention relates to esters of pantothenic acid, intermediatesthereof, and processes for their production. This application is adivision of our copending application Serial No. 605,193, filed July 14,1945, now abandoned, which, in turn, is a division of application SerialNo. 386,- 942', filed April 4, 1941, now abandoned.

Pantothenic acid occurs Widely in nature and has recently becomeavailable by synthetic methods. According to the most widely usedmethods of preparation, laevorotatory whydroxy-fl c-dimethylbutyrolactone is reacted with fi-alanine or some derivative crp-alanine, such as its so.di-= um salt or its ester.

However, pantothenic acid is soluble mainly in polar solvents, such aswater and the lower al cohols. For certain types of use it is desired touse pantothenic acid in an oil medium, and for this purpose the ordinarypantothenic acid of commerce is not suited.

We have discovered that esters of pantothenic acid of the followingstructure R1OCH2C (CH3) 2CH( 0R2) CONHCHzCI-IzCOORs where R1 is an acylgroup or hydrogen, R2 is an acyl group, and R3 is hydrogen or an allcylgroup are soluble in oil. Esters of. this type may be formed by reactingan ester or" a-gamma dihydroxy-BJi-dimethyl butyric acid chloride withan ester of b-alanine. The butyric acid chloride can be made by reactinga-hydroxy-dB-dimethylgamma-butyrolaetone with liquid ammonia givea-garnrna-dihydroxy-fl,,c-dimethyl butyramide, which is then reactedwith a lower aliphatic carboxylic acid anhydride or a lower aliphaticcarboxylic acid chloride to give the corresponding ester of the amide.The latter product is reacted with amyl nitrite to produce thecorresponding ester of a-gamma-dihydroxy-Bfi-dimethyl-butyric acid,which can be represented by the formula:

CH2(OOCR) C(CH3) 2CH(OOCR') COOH wherein R and R. are lower alkylradicals, and from which the desired acid chloride may be obtained bytreatment with thionyl chloride.

For certain uses an ester of the following structure is desired:

R4O-CH2Q CH3) 2CHOHCONHCH2CH2COOR3 fi-alanine or one of its derivativesto form a monocarbobenzyloxy ester of pantothenic acid. The latter maythen be treated with the desired esterifying agent, and the resultingdiester of pantothenic acid hydrogenated to remove the carbobenzyloxyradical. This process may be illustrated as follows:

00001 onzownmouono=o c001, CHzC(OHa)2JHC=.,O

fl-alauine or derivative R CHzC (CH3)2CHOHO ONHCHzCHzCO 0R5 The abovediagram also shows how the monocarbobenzyloxy ester of the lactone isprepared.

We have also discovered that mono esters of pantothenic acid orderivatives having the ester residue in the a position of the butyricacid residue may be prepared by treating the lactone with an esterifyingagent such as an acid chloride or acid halide to esterify the freehydroxyl group of the lactone, and reacting this lactone containingasingle ester group with p-alanine or its derivatives.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given byway of illustration and not of limitation.

Example 1 13.6 grams of a-hYdI'OXY-Bfl-dilnthYlgamma-butyrolactone andcc. of liquid ammonia are sealed in a bomb tube (using a Dry Ice bath tokeep the ammonia liquid until the tube is 44.1 grams ofa,gamma-dihydroxy-p,p3-dimethylbutyramide are dissolved in '75 cc. ofpyridine, and '71 cc. (25% excess) of acetic anhydride are added. Thesolution is heated for one-half hour on the steam bath, and thenconcentrated under reduced pressure. The residue is distilled from awide side armed flask at 2 mm. pressure and bath temperature of 170(vapor temperature 155). The yield of very viscous liquid,iii-gammadiacetoxy-pflfl-dimethylbutyramide, is 67.2 g. (97%).

(a) =0.7 (in CHCls; C=2.848%) (a) =+6.2, +6.8 (in ether; C=2.432% and5.292% respectively) (a) =+6.1 (in ethyl acetate; C=1.798%) (a) =5.4 (indioxane; C=1.486%) (a) =4.5 (in abs. ethanol; C=1.998%) (a) =9.9 (inwater; C=2.223%) 11.54 grams ofa,gamma-diacetoxy-,8,;3-dimethylbutyramide are dissolved inapproximately 50 cc. of glacial acetic acid, and 20 cc. of amyl nitriteare added. The solution is heated on the steam bath for 80 minutes, thenconcentrated under reduced pressure, and the residue taken up in waterin which it dissolves very slowly. The solution is made just alkalinewith sodium hydroxide and extracted with chloroform. The aqueoussolution is acidified to pH 2 and theagamma-diacetoxy,6,fl-dimethylbutyric acid extracted with chloroform.The chloroform solution is concentrated to a syrup under 2 mm. pressure.The product weighs 7.52 grams, titrating for 90% acid. It is distilledat 10- mm. at 100 bath temperature. Three fractions are taken, each ofwhich contains nitrogen by qualitative analysis. The third fraction isrepurified by dissolving in sodium hydroxide as described above, thenredistilled, and a-gamma-diacetoxy-Bfi-dimethylbutyric acid is obtainedfree of nitrogen. (a) =2.6 (C=1.512 in methanol); in ether).

4.4 grams of a-gamma-diacetoxy-p,e-dimethylbutyric acid are treated with2.77 cc. of thionyl chloride, heated on a steam bath for hour, and thenthe excess of thionyl chloride is removed under vacuum. The residue isdissolved in 5 cc. of pyridine and 2.23 grams of fl-alanine ethyl esterare added. Heat is evolved and the solution becomes slightly colored.After standing for '72 hours, the excess pyridine is removed bydistillation under vacuum, the syrup dissolved in chloroform, andextracted first with dilute hydrochloric acid, then with sodiumbicarbonate solution, and finally dried over calcium chloride. Afterremoval of the chloroform, the syrup is distilled in a sublimationapparatus at mm. pressure, and a bath temperature of 110-120. Yield ofethyl N-(a-gamma-diacetoxy-fi,B-dimethylbutyryl)-fi-aminopropionate 3.06grams (48.5%). (a) =|24.2 (C=2.08% in ether).

A solution of 0.11 gram of the above ester is dissolved in 10 cc. of 0.5N-barium hydroxide and allowed to stand at room temperature for onehour. The barium ion is removed quantitatively as the sulfate, and thesolution brought to pH 7.5 with sodium hydroxide. Aliquot parts of thesolution are assayed microbiologically and found to contain 50% of thetheoretical amount of pantothenic acid.

Example 2 0.62 gram of a-p-nitrobenzoxy-[ifi-dimethylgamma-butyrolactoneis heated with 0.233 gram of sodium fl-alaninate for one hour on a steambath. After a few minutes, the mixture becomes gummy, and solidifies toa brittle mass on cooling. The material is dissolved in 10 cc. of water,with deposition of crystals of starting material. The filtrate isacidified with hydrochloric acid, and a gummy precipitate separates. Itis readily soluble in alcohol, and is reprecipitated as an oil upon theaddition of water. On standing overnight, the mono nitrobenzoate ofpantothenic acid crystallizes, and is recrystallized from acetone uponthe addition of water, M. P. 137-138"; (a) =l-4.5 (in alcohol, C=0.78%).

Example 3 A benzene solution containing 6 grams ofahydroxy-pfi-dimethyl-gamma-butyrolactone and 8.65 grams of antipyrineare added to a benzene solution containing 4.6 grams phosgene.Crystalline antipyrine hydrochloride separates. After 15 minutes, 5grams benzyl alcohol and 8.65 grams antipyrine dissolved together inbenzene are added to the above solution whereupon heat is evolved, andadditional antipyrine hydrochloride separates out. The mixture is heatedon a steam bath for 15 minutes, then filtered, the filtrate washed threetimes with water, and then dried over calcium chloride. Afterconcentration under reduced pressure, the syrup commences tocrystallize. It is recrystallized by dissolving in water, and adding alittle alcohol until tubidity is produced. On coolinga-carbobenzyldioxy-p,{3-dimethyl-gamma-butyrolactone separates, M. P.78; yield 5.05 grams (41.8%) (a) =+12.3 (in 95% alcohol, C=2.1%).

1.9 grams of freshly distilled [El-alanine ethyl ester are mixed with4.2 grams of a-carbobenzyldioxy fifi-dimethyl butyrolactone, and heatedon a steam bath for 1 hours. It is then shaken with water and extractedwith ether. After washing with dilute hydrochloric acid and water, theether extract is dried over calcium chloride, and filtered withcharcoal. The oily residue is distilled between -150" bath temperatureat 4 10- mm. pressure.

Example 4 26 grams of acetyl lactone are mixed with 17.7

grams of fi-alanine ethyl ester, and heated on the steam bath for twohours. It is then distilled from a Wide armed distilling flask at 10*mm.

'A forerun up to totaling 12 grams is obtained. The main crop distilledat 155-160. The yield of monoacetyl ethyl pantothenate is 28 grams(64.5%).

We wish it to be understood that we do not desire to be limited to theexact details described, for obvious modifications will occur to aperson skilled in the art.

We claim:

1. The process of preparing a,Y-diacyloxy- ,Bp-dimethyl-butyric acidwhich comprises reacting uy-dihydroxy 5,;9-dimethyl-butyramide with acompound selected from the class which consists of lower aliphaticcarboxylic acid anhydrides and lower aliphatic carboxylic acidchlorides, and reacting the compound thus obtained with amyl nitrite.

2. The process of preparing a,Y-diacetoxy-{J,pdimcthyl-butyric acidwhich comprises reacting a,"/-dihydroxy pfi-dimethyl butyramide withacetic anhydride in the presence of pyridine and reacting the compoundthus obtained with amyl nitrite, said reaction being carried out insolution in glacial acetic acid.

3. The process of preparing a,'Y-dla.O6t0Xy-,8,fi-

with 5 REFERENCES CITED The following references are of record in thefile of this patent:

UNITED STATES PATENTS Name Date Woolley Mar. 20, 1945 OTHER REFERENCESNiimber 10 Harris: Jour. Am. Chem. Soc. 63, pages 2662- Certificate ofCorrection Patent No. 2,519,462 August 22, 1950 STANTON A. HARRIS ET AL.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as follows:

Column 5, line 2, for diacetoxy read dihydrozy; and that the saidLetters Patent should be read as corrected above, so that the same mayconform to the record of the case in the Patent Office.

Signed and sealed this 14th day of November, A. D. 1950.

THOMAS F. MURPHY,

Assistant Gommz'ssioner of Patents.

1. THE PROCESS OF PREPARING A,Y-DIACYLOXYB,B-DIMETHYL-BUYRIC ACID WHICHCOMPRISES REACTING A, Y-DIHYDROXY-B,B-DIMETHYL-BUTYRAMIDE WITH ACOMPOUND SELECTED FROM THE CLASS WHICH CONSISTS OF LOWER ALIP-HATICCARBOXYLIC ACID ANHYDRIDES AND LOWER ALIPHATIC CARBOXYLIC ACIDCHLORIDES, AND REACTING THE COMPOUND THUS OBTAINED WITH AMYL NITRITE.